The invention is concerned especially with benzazepinone derivatives of formula I 
wherein 
R3 is hydrogen, alkyl, cycloalkyl, aralkyl, aryl or carboxyalkyl;
R4 is alkyl or aralkyl;
R5 is hydrogen, alkyl, aryl, heterocyclyl or xe2x80x94COxe2x80x94NHxe2x80x94R8;
R6 is hydrogen or 
R7 is hydrogen, alkyl, cycloalkyl or aralkyl;
R8 is alkyl, cycloalkyl, aralkyl or aryl;
R9 is hydrogen, alkyl, cycloalkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen or alkyl or R10 and R11 together with the N-atoms to which they are attached form a 5- to 6-membered heterocyclic ring which can be alkyl-substituted;
X is xe2x80x94CH(R3)xe2x80x94;
Z is xe2x80x94N(R7)xe2x80x94 or oxygen, wherein Y is xe2x80x94COxe2x80x94 when Z is xe2x80x94N(R7)xe2x80x94 and Y is xe2x80x94CH(R9)xe2x80x94 when Z is oxygen;
m, n and p are zero or whole positive numbers, wherein m is 2 to 5; n is zero or 1; p is zero or 1;
and their pharmaceutically usable salts and esters.
The compounds of formula I and their pharmaceutically usable salts and esters are novel and have valuable pharmacological properties. In particular, they inhibit the binding of adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, etc.) on the surface of various types of cell. All of the compounds of formula I that were tested inhibited the binding of fibrinogen to the vitronectin receptor xcex1vxcex23 in the assay described below. Therefore these compounds can be used as vitronectin receptor agonists in the treatment and prophylaxis of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors. In particular, they can be used as vitronectin receptor antagonists in the prophylaxis or treatment of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, intermediates, pharmaceutical compositions, medicaments containing the said compounds, their salts or esters, the use of the said compounds, solvates and salts for the prophylaxis and/or therapy of illnesses, especially in the treatment or prophylaxis of, for example, neoplasms, tumor metasis, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi, and the use of the said compounds and salts for the production of medicaments for the treatment or prophylaxis of, for example, neoplasms, tumor metasis, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
In the present description the term xe2x80x9calkylxe2x80x9d, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1-4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, tert.butyl and pentyl.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl and particularly cyclopentyl.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, signifies a group of the formula alkyl-Oxe2x80x94 in which the term xe2x80x9calkylxe2x80x9d has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.
The term xe2x80x9carylxe2x80x9d, alone or in combination, signifies a phenyl or naphthyl group which optionally carries one or more substituents each independently selected from alkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, aminocarbonyl, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert.butoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl and 2-naphthyl. Preferred are carboxyphenyl, hydroxyphenyl and fluoro-phenyl and particularly phenyl.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, signifies an alkyl or cycloalkyl group as previously defined in which one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl, benzyl substituated with hydroxy or halogen, preferably fluorine. Particularly preferred is benzyl.
The term xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, signifies a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. If desired, it can be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo etc. and/or on a secondary nitrogen atom (i.e. xe2x80x94NHxe2x80x94) by alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e.xe2x95x90Nxe2x80x94) by oxido, with halogen, alkyl, cycloalkyl and alkoxy being preferred. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrazoyl, imidazoyl (e.g. imidazol-4-yl and 1-benzyloxycarbonyl-imidazol-4-yl), pyrazoyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl, indolyl (e.g. 2-indolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl and 1-oxido-2-quinolyl), isoquinolyl (e.g. 1-isoquinolyl and 3-isoquinolyl), tetrahydroquinolyl (e.g. 1,2,3,4-tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (e.g. 1,2,3,4-tetrahydro-1-oxo-isoquinolyl) and quinoxalinyl. Preferred are 5- or 6-membered rings, especially pyridyl. Particularly preferred is 3-pyridyl.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, xe2x80x94NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably amino, dimethylamino and diethylamino and particularly primary amino.
The term xe2x80x9chalogenxe2x80x9d signifies fluorine, chlorine, bromine or iodine and preferably chlorine or bromine and particularly chlorine.
The term xe2x80x9ccarboxyxe2x80x9d, alone or in combination, signifies a xe2x80x94COOH group.
The term xe2x80x9ccarboxyalkylxe2x80x9d alone or in combination, signifies an alkyl group as previously described in which one hydrogen atom has been replaced by a carboxy group. The carboxymethyl group is preferred and particularly carboxyethyl.
The term xe2x80x9camino protecting groupxe2x80x9d, alone or in combination, signifies any conventional amino protecting group. Examples of amino protecting groups include BOC and Cbz.
Examples of physiologically usable salts of the compounds of formula I are salts with physiologically compatible mineral acids such hydrochloric acid, sulphuric acid or phosphoric acid; or with organic acids such as methanesulphonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with free carboxy groups can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, alkali earth metal, ammonium and alkylammonium salts such as the Na, K, Ca or tertramethylammonium salt. The compound of formula I can also be present in the form of zwitterions.
The invention expressly includes pharmaceutically suitable derivatives of the compounds of formula I. For example, the COOH groups in R1 and R3 can be esterified. The alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl, butyl, benzyl and (R/S)-1-((isopropoxy-carbonyl)-oxy)-ethyl esters are preferred esters. The methyl, ethyl and tert.butyl esters are especially preferred.
The compounds of formula I can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
The compounds of formula I can contain several asymmetric centres and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
In a preferred embodiment of the present invention R1 is 
In a further preferred embodiment R1 is 
Also preferred are compounds according to formula I, wherein R2 is 
Further preferred are compounds according to formula I, wherein R2 is 
Another preferred embodiment of the invention comprises compounds of formula I, wherein R3 is hydrogen, alkyl, aralkyl or carboxyalkyl, preferrably hydrogen, propyl, butyl, carboxyethyl, benzyl or benzyl substitued with hydroxy. Particularly preferred examples for R3 are hydrogen, 2-propyl, 2-butyl, 2-carboxyethyl, benzyl and p-hydroxy-benzyl.
Further preferred compounds of the present invention are those, wherein R4 is butyl, benzyl or benzyl substituted with halogen, particularly with fluorine. Particularly preferred examples for R4 are n-butyl, benzyl and p-fluoro-benzyl.
Also preferred are the compounds according to formula I, wherein R5 is hydrogen, methyl, phenyl, pyridyl or xe2x80x94COxe2x80x94NHxe2x80x94R8.
Another preferred aspect of the present invention are compounds according to formula I, wherein R6 is hydrogen or xe2x80x94NHxe2x80x94COxe2x80x94NH-benzyl.
Also preferred are compounds according to formula I, wherein R7 is hydrogen or alkyl, particularly preferred hydrogen or methyl.
Another preferred embodiment of the present invention are compounds of formula I, wherein R8 is aryl, preferably phenyl or substituted phenyl. Particularly preferred is phenyl substituted with carboxy.
Likewise preferred are compounds according to formula I, wherein R9 is hydrogen or aryl. Particularly preferred is hydrogen and phenyl.
Also preferred are compounds of formula I in which R10 and R11 together with the N-atoms to which they are attached form an imidazolidine or a hexahydropyrimidine ring. Particularly preferred are the compounds according to formula 1, wherein R10 and R11 are hydrogen.
Another preferred object of the present invention comprises compounds of formula I, wherein p is 1 when Z is oxygen.
Other preferred compounds of formula I are those, wherein m is 2 to 4, preferably m is 3 to 4.
Further preferred compounds according to formula I are those, wherein n is 1.
Also preferred compounds of formula I are those in which p is 1.
Further preferred are compounds of formula I, wherein Z is xe2x80x94N(R7)xe2x80x94.
Another preferred embodiment of the present invention are compounds of formula I, wherein Z is oxygen.
In one embodiment of the derivative of formula I the compound has the formula 
wherein R3 is hydrogen, alkyl, unsubstituted benzyl, hydroxy-substituted benzyl, or carboxyalkyl; R5 is hydrogen, alkyl having from 1 to 4 carbon atoms, or unsubstituted phenyl; and R7 is hydrogen or alkyl having from 1 to 4 carbon atoms. In a more specific embodiment R3 is hydrogen or alkyl. Examples of such compounds include (R,S)-3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-3-phenyl-propionic acid; 3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid; 3-(R,S)-{2-[7-(3-benzyl-ureido)-(3-(S,S)-sec-butyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid; and 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid. In another more specific embodiment R3 is unsubstituted benzyl, hydroxy-substituted benzyl or carboxyalkyl. Examples of such compounds include 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid; 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid; 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid; 3-(R,S)-{2-[3-(S)-benzyl-7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid; and 3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo [e][1,4]diazepin-4-yl]-acetylamino}-butyric acid.
In another embodiment of the derivative of formula I the compound has the formula 
wherein m is from 2 to 5; n is zero or 1; R6 is hydrogen or 
R4 is aralkyl; and R7 is hydrogen or alkyl having from 1 to 4 carbon atoms. Examples of such compounds include (R,S)-6-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-[4-(3-benzyl-ureido)-phenyl]-hexanoic acid; 6-[7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-hexanoic acid; and (R,S)-6-[7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-hexanoic acid.
In another embodiment of the derivative of formula I the compound has the formula 
wherein R5 is hydrogen or unsubstituted phenyl; and R7 is hydrogen or alkyl having from 1 to 4 carbon atoms. Examples of such compounds include 3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid; and 3-[2-(7-guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-propionic acid.
In another embodiment of the derivative of formula I the compound has the formula 
wherein R2 is 
R4 is unsubstituted benzyl; and R7 is alkyl having from 1 to 4 carbon atoms. Examples of such compounds include (R,S)-3-[2-[6-(3-benzyl-ureido)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetylamino]-3-phenyl-propionic acid; and (R,S)-3-[2-(6-guanidino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid.
In another embodiment of the derivative of formula I the compound has the formula 
wherein
R4 is alkyl, unsubstituted benzyl or halo-substituted benzyl;
R5 is hydrogen, unsubstituted phenyl, pyridyl or 
R8 is carboxy-substituted phenyl; and R9 is hydrogen or unsubstituted phenyl. In a more specific embodiment R5 is hydrogen and R9 is hydrogen. Examples of such compounds include 3-{2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-propionic acid. In another more specific embodiment R5 is unsubstituted phenyl. Examples of such compounds include (R,S)-3-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-phenyl-propionic acid; and (R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4yl]-acetylamino}-3-phenyl-propionic acid. In another more specific embodiment R5 is 3-pyridyl. Examples of such compounds include (R,S)-3-{2-[7-(3-benzyl-3-methyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid hydrochloride; (R,S)-3-{2-[7-(3-butyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid; and (R,S)-3-(2-{7-[3-(4-fluoro-benzyl)-ureido]-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl}-acetylamino)-3-pyridin-3-yl-propionic acid. In another more specific embodiment R5 is xe2x80x94C(O)NHR8 and R8 is carboxy-substituted phenyl. Examples of such compounds include (S)-2-[2-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-carboxy-propionylamino]-benzoic acid.
Examples of preferred compounds of formula I are:
(R,S)-3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-3-phenyl-propionic acid;
(R,S)-3-[2-(7-guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid hydrochloride;
3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid;
3-[2-(7-guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-propionic acid hydrochloride;
(R,S)-6-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-[4-(3-benzyl-ureido)-phenyl]-hexanoic acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
3-(R;S)-{2-[7-(3-benzyl-ureido)-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-(3-(S,S)-sec-butyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(2-carboxy-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid
3-(R,S)-{2-[3-(S)-benzyl-7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid;
(R,S)-3-[2-[6-(3-benzyl-ureido)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetylamino]-3-phenyl-propionic acid);
(R,S)-3-[2-(6-guanidino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid;
3-{2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-propionic acid;
(R,S)-3-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-phenyl-propionic acid;
(R,S)-3-{2-[7-(3-benzyl-3-methyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid hydrochloride;
(S)-2-[2-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-carboxy-propionylamino]-benzoic acid as acetate salt;
(R,S)-3-{2-[7-(3-butyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid;
(R,S)-3-(2-{7-[3-(4-fluoro-benzyl)-ureido]-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl}-acetylamino)-3-pyridin-3-yl-propionic acid;
(R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
6-[7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4yl]-hexanoic acid;
(R,S)-6-[7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-hexanoic acid.
Examples of particularly preferred compounds of formula I are
(R,S)-3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-3-phenyl-propionic acid;
3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid;
(R,S)-6-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-[4-(3-benzyl-ureido)-phenyl]-hexanoic acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
3-(R,S)-{2-[7-(3-benzyl-ureido)-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid;
(R,S)-3-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-phenyl-propionic acid;
(R,S)-3-{2-[7-(3-benzyl-3-methyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid hydrochloride;
(R,S)-3-{2-[7-(3-butyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid;
(R,S)-3-(2-{7-[3-(4-fluoro-benzyl)-ureido]-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl}-acetylamino)-3-pyridin-3-yl-propionic acid;
(R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
(R,S)-6-[7-(3-benzyl-ureido)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-hexanoic acid.
Processes for the manufacture of compounds of formula I are an object of the invention.
The substituents and indices used in the following Schemes have the significances given above unless indicated to the contrary.
Compounds of formula II 
can be prepared according to the Schemes 1 to 4.
The corresponding quinazoline-2,4-diones might be prepared as shown in Scheme 1. 
Reaction of a substituted 3,1-benzoxazine-2,4-dione III with glycine ethyl ester followed by treatment with ethylchloroformate and then with base (e.g. KOH aq.) gave the acid IV (M.Sxc3xcsse and S. Johne, Monatshefte. Chemie, 1987, 118, 71-79). Compounds of formula III, wherein R7 is alkyl, cycloalkyl or aralkyl can be obtained by reacting a compound according to formula III, wherein R7 is hydrogen with the corresponding alkyl halide, cycloalkyl halide or aralkyl halide in the presence of NaH in THF or dioxan. The corresponding compound III, wherein R7 is hydrogen is known in the art.
Nitration of IV followed by coupling with a 3-substituted beta-alanine ester and catalytic hydrogenation led to the formation of V (Scheme 2). 
Reaction of V with an isocyanate R4xe2x80x94Nxe2x95x90Cxe2x95x90O followed by ester hydrolysis produced the carboxylic acid VI.
By using an amine of type VII instead of glycine ethyl ester the intermediate VIII might be prepared (Scheme 3). 
Compounds according to formula X, wherein R66 means 
can be obtained by the reaction of compounds of formula X, wherein R66 is NH2 with an isocyanate R4xe2x80x94Nxe2x95x90Cxe2x95x90O in the presence of a base.
A related sequence of reactions as shown in Scheme 2 was then applied to complete the synthesis of compounds of type X (via IX).
For the preparation of the guanidine derivatives XI the corresponding amines V (Scheme 2) or IX (R66=H, NHCONHR4, Scheme 3) might be reacted with N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (R. J. Bergeron and J. S. McManis, J. Org. Chem., 1987, 52, 1700-1703) in the presence of Hg(OAc)2. Removal of the protective groups with TFA followed by ester hydrolysis gave the desired guanidino carboxylates XI (Scheme 4). 
can be prepared according to the Schemes 5 to 8.
Scheme 5 illustrates the method used for the preparation of the benzodiazepinediones XVI and XVII. Briefly, in an xe2x80x9cUgi-typexe2x80x9d four component reaction (see e.g. T. A. Keating and R. W. Armstrong, J. Org. Chem., 1996, 61, 8935-39) a 3-substituted 3-isocyano-propionic acid was reacted with 5-N-acetylamino-2-azidobenzoic acid (obtained by reaction of 5-N-acetylamino-2-aminobenzoic acid with sodium nitrite in the presence of HCl) and an adequately protected alpha amino acid derivative (e.g. t-butylester or benzylester) in the presence of formaldehyde to give the intermediate XIV. Upon treatment with polymer bound triphenylphosphine followed by heating and cleavage of the acetamide group the bicyclic amine XV was obtained. Completion of the synthesis of the corresponding urea (XVI) or guanidino (XVII) derivatives required methods already described in Schemes 2 and 3 or Scheme 4, respectively. The corresponding 3-substituted 3-isocyano-propionic acid can be obtained by formylating the corresponding amines in the presence of formic acid and silicon hydride (Jerry March, Wiley-Interscience, 4. edition, page 419). The isonitriles can also be prepared by elimination of water from the corresponding N-alkylformamides according to Ugi, Angew. Chem. Int. Ed. Engl. 4, 472-484 (1965). 
In a rather similar way, illustrated in Scheme 6, the benzodiazepinediones XXI and XXII could be prepared. In the event, an omega amino acid XVIII was reacted with 5-N-acetylamino-2-azidobenzoic acid (obtained by reaction of 5-N-acetylamino-2-aminobenzoic acid with sodium nitrite in the presence of HCl) in the presence of an aldehyde as well as an isonitrile to give XIX. The completion of the synthesis of XXI and XXII followed the same route as described in Scheme 5. The preparation of XVIII is described in EP 98100006. Briefly, triethylphosphonoacetate was reacted with (4-oxo-4-phenyl-butyl)carbamic acid t-butylester in the presence of sodium ethoxide. The resulting product was reduced by catalytic hydrogenation and the protective group cleaved upon treatment with HCl in EtOAc to give (R,S)-6-amino-3-phenyl-hexanoic acid ethyl ester which could be hydrolysed to the corresponding acid. 
In case R7 is not hydrogen the routes illustrated in Scheme 7 and 8 might be used to prepare the desired benzodiazepinediones (for a similar strategy see e.g. B. K. Blackburn et al., J. Med. Chem. 1997, 40, 717-729). Specifically, a substituted isatoic acid anhydride (see e.g. G. M. Coppola, J. Heterocyclic Chem. 1986, 23, 233) was converted to the intermediates XXIII or XXIX by the three step sequence shown. Nitration followed by reduction of the nitro group yielded the amine XXIV (Scheme 7). The desired urea derivatives XXVII and the guanidino derivative XXVIII were then prepared via XXV and XXVI, respectively, using methods already discussed in Schemes 2, 3, and 4. A closely related strategy was applied to the completion of the synthesis of the derivatives XXX and XXXI (Scheme 8). 
can be prepared according to Scheme 9.
The benzoxazoline derivatives XXXIV and XXXV might be prepared by the general methodology outlined in Scheme 9. Briefly, 5-N-Cbz-2-hydroxybenzoic acid or 5-nitro-2-hydroxybenzoic acid might be coupled with the corresponding omega amino acid ester derivatives using standard reaction conditions (e.g. in the presence of HBTU and NMM). Reaction of the benzamides obtained with an aldehyde R9xe2x80x94CHO (see e.g. T. Miyake et al., Tetrahedron Letters 1996, 37, 3129 or J. M. Takacs et al., Tetrahedron Letters 1989, 30, 7321) followed by either removal of the protective group or reduction of the nitro group yielded the amino derivatives XXXIII. For the completion of the synthesis of the benzoxazoline derivatives XXXIV and XXXV the methods described in Schemes 2, 3, and 4 could be applied. 
can be prepared according to Schemes 10 and 11.
Scheme 10 is illustrative of the methodology useful for preparing the benzoxazepine derivatives XXXX and XXXXI. Specifically, coupling of 2-fluoro-5-nitro-benzoic acid (Aldrich) with a substituted (2-hydroxy-ethylamino)-acetic acid derivative of type XXXVII (see e.g. G. Breipohl et al., Tetrahedron 1997, 53, 14671 and H. Kotsuki et al., Chem Lett 1994, 11, 2159), followed by cyclization and ester cleavage afforded the intermediate XXXVIII. Standard coupling of XXXVIII with a 3-substituted beta-alanine ester followed by reduction of the aromatic nitro group led to the formation of the chain elongated amine XXXIX. Completion of the synthesis of the corresponding guanidino (XXXX) or urea (XXXXI) derivatives required methods already described in Scheme 4 or Schemes 2 and 3, respectively. 
Instead of the glycine derivative XXXVII (Scheme 10) the amino esters XXXXIII could be employed (Scheme 11). These, in turn, might be prepared by reaction of XXXXII with
i) a corresponding epoxide (see e.g. S. V. D""Andrea et al., J. Org. Chem. 1991, 56, 3133 or Q. Liu et al., Synlett 1995, 1037) or
ii) an alpha bromo ketone followed by reduction with NaBH4 (see e.g. M. Ohba et al., Chem. Pharm. Bull. 1992, 40, 2543) or
iii) an alpha hydroxy ketone in the presence of NaBH4 (see e.g. M. Peerzada, Org. Prep. Proceed. Int. 1985, 17, 267).
The completion of the synthesis of XXXXIV or XXXXV ( Scheme 11) was achieved according to the methodology illustrated in Scheme 10. 
A preferred process for the preparation of a compound according to formula I, comprising one of the following steps:
5 a) reacting a compound of formula XXXXV 
xe2x80x83with an isocyanate of the formula R4xe2x80x94Nxe2x95x90Cxe2x95x90O,
wherein R 12 is 
xe2x80x83and R3 to R11, X, Y, Z, m,n and p are as defined above for formula I, and then treating the resulting compound to hydrolyze the resulting ester group contained in R12; or
b) reacting a compound of the formula XXXXV with guanylation agent (see for example Yaw Fui Yong et al., Tetrahedron Letters, 1999, 40, 53-56), preferably N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea in the presence of Hg(OAc)2 or HgCl2, wherein R3 to R12, X, Y, Z, m,n and p are defined as under a), and then treating the resulting compound to hydrolyze the resulting ester group contained in R12; or
c) reacting a compound of formula XXXXVI 
xe2x80x83with H2Nxe2x80x94CH(R5)xe2x80x94CH2xe2x80x94COOR4 under coupling conditions (e.g. HBTU in the presence of NMM), wherein R13 is 
xe2x80x83and R3 to R11, X, Y, Z, m,n and p are as defined above for formula I. The protecting group in R13 is an amino protecting group such as for example Cbz (see e.g. R. J. Bergeron and J. S. Mc Manis, J. Org. Chem. 1987, 52, 1700-1703) and preferably BOC; treating the resulting compound to hydrolyze the ester group containing R4 and yield the corresponding carboxylic acid, and when R13 is the second group shown above, treating the resulting compound to remove the amino protecting groups. Removal of the amino protecting groups can be done before, at the same time, or after hydrolysis of the ester groups. The protecting group Cbz can be removed as described in Bergeron and McManis. BOC can be removed under acid conditions.
The invention also includes intermediates of formula XXXXV and XXXXVI 
and R3 to R11, X, Y, Z, m,n and p are as defined above for compounds of formula I.
In an embodiment of the compound of formula XXXXV, X is xe2x80x94CH(R3)xe2x80x94; R3 is hydrogen, alkyl, aralkyl, or carboxyalkyl; R12 is 
R4 is alkyl; and R5 is hydrogen, alkyl or aryl. Examples of such compounds include 3-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionic acid ethyl ester. In a more specific embodiment, in addition Z is xe2x80x94N(R7)xe2x80x94; Y is xe2x80x94COxe2x80x94; and R7 is hydrogen or alkyl. Examples of compounds of such more specific embodiment include (R,S)-3-[2-(6-amino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester. In still more specific embodiments R7 is hydrogen; and p is 1. Examples of such compounds in which R3 is alkyl include 3-(R,S)-[2-(7-amino-3-(S,S)-sec-butyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid methyl ester; and 3-(R,S)-[2-(7-amino-3-(S)-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-butyric acid methyl ester. Examples of such compounds in which R3 is aralkyl include 3-(R,S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid methyl ester; 3-(R,S)-[2-(7-amino-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid methyl ester; 3-(R,S)-{2-[7-Amino-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]-diazepin-4-yl]-acetylamino}-butyric acid methyl ester; and 3-(R,S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid methyl ester. Examples of such compounds in which R3 is carboxyalkyl include 3-(R,S)-{2-[7-Amino-3-(S)-(2-methoxycarbonyl-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid methyl ester.
In an embodiment of the compound of formula XXXXVI, Z is xe2x80x94N(R7)xe2x80x94; R7 is alkyl; Y is xe2x80x94COxe2x80x94; X is xe2x80x94CH(R3)xe2x80x94; R3 is hydrogen; p is 1; and R4 is alkyl. Examples of such compounds include [7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid ethyl ester; and (7-N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester.
Especially preferred intermediates are:
(1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester;
(7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester;
[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid ethyl ester;
[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetic acid;
(R,S)-3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-3-phenyl-propionic acid ethyl ester;
(7-N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester;
(7-N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid;
(R,S)-3-[2-(7-(N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester;
3-[2-(1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-propionic acid ethyl ester;
3-[2-(1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl-acetylamino]-propionic acid ethyl ester;
3-[2-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino]-propionic acid ethyl ester;
3-[2-(7-(N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino-propionic acid ethyl ester;
(R,S)-6-(1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-phenyl-hexanoic acid ethyl ester;
(R,S)-6-(1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-(4-nitro-phenyl)-hexanoic acid ethyl ester;
(R,S)-6-[7-(3-benzyl-ureido)-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-[4-(3-benzyl-ureido)-phenyl]-hexanoic acid ethyl ester;
3-(R,S)-{2-[7-acetylamino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid methyl ester;
3-(R;S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid methyl ester;
3-(R;S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid;
3-(R,S)-[2-(7-acetylamino-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid methyl ester;
3-(R,S)-[2-(7-acetylamino-3-(S,S)-sec-butyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-3-phenyl-propionic acid methyl ester;
3-(R,S)-{2-[7-acetylamino-3-(S)-(2-methoxycarbonyl-ethyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-3-phenyl-propionic acid methyl ester;
3-(R,S)-{2-[7-Amino-3-(S)-benzyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid methyl ester;
3-(R,S)-{2-[7-amino-3-(S)-(4-hydroxy-benzyl)-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-acetylamino}-butyric acid;
3-(R,S)-[2-(7-amino-3-(S)-isopropyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetylamino]-butyric acid;
(R,S)-3-[2-[6-(3-benzyl-ureido)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetylamino]-3-phenyl-propionic acid);
(1-methyl-6-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid;
(R,S)-3-[2-(1-methyl-6-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester;
(R,S)-3-[2-(6-amino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester;
(R,S)-3-[2-[6-(3-benzyl-ureido)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-acetylamino]-3-phenyl-propionic acid ethyl ester;
(R,S)-3-[2-(6-guanidino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid;
(R,S)-3-[2-(6-(N2, N3-bis(tert-butoxycarbonyl)guanidino-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester;
[(2-fluoro-5-nitro-benzoyl)-(2-hydroxy-ethyl)-amino]-acetic acid tert-butyl ester;
(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetic acid tert-butyl ester;
(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetic acid;
3-[2-(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionic acid ethyl ester;
3-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionic acid ethyl ester;
3-{2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-propionic acid ethyl ester;
(R,S)-3-[2-(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-phenyl-propionic acid ethyl;
(R,S)-3-[2-[7-(3-benzyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino]-3-phenyl-propionic acid ethyl ester;
(R,S)-3-{2-[7-(3-benzyl-3-methyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid ethyl ester;
(S)-2-[3-benzyloxycarbonyl-2-[2-(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-propionylamino]-benzoic acid benzyl ester;
(S)-2-[2-[2-(7-amino-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-carboxy-propionylamino]-benzoic acid;
(R,S)-3-[2-(7-nitro-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-pyridin-3-yl-propionic acid ethyl ester;
(R,S)-3-{2-[7-(3-butyl-ureido)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-pyridin-3-yl-propionic acid ethyl ester;
(R,S)-3-(2-{7-[3-(4-fluoro-benzyl)-ureido]-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl}-acetylamino)-3-pyridin-3-yl-propionic acid ethyl ester;
(R,S)-[(2-fluoro-5-nitro-benzoyl)-(2-hydroxy-2-phenyl-ethyl)-amino]-acetic acid tert-butyl ester;
(R,S)-(7-nitro-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetic acid tert-butyl ester;
(R,S)-3-[2-(7-nitro-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-acetylamino]-3-phenyl-propionic acid ethyl ester;
(R,S)-3-{2-[7-(3-benzyl-ureido)-5-oxo-2-phenyl-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-acetylamino}-3-phenyl-propionic acid ethyl ester;
6-(7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-hexanoic acid methyl ester;
(R,S)-6-[7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-3-phenyl-hexanoic acid ethyl ester.
The compounds of formula I described above for use as therapeutically active substances are a further object of the invention.
Also an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors.
Likewise an object of the invention are pharmaceutical compositions containing a compound of formula I described above and a therapeutically inert carrier. The invention likewise relates to a pharmaceutical composition as previously described, which additionally contains one or more compounds of formula I or additionally one or more compounds selected from the group comprising anticoagulants, fibrinolytics as well as medicaments for the prophylaxis and therapy of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors.
An object of the invention is also the use of the compounds described above for the production of medicaments, particularly for the treatment or prophylaxis of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors.
Also an object of the invention is the use of one of the compounds described above for the production of medicaments e.g. for the treatment or prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.
A further object of the invention comprises compounds which are manufacturable according to one of the described processes.
Likewise an object of the invention are methods for the treatment and prophylaxis of illnesses which are caused by a malfunction of the binding of adhesive proteins to vitronectin receptors and which are comprised by the administration of an effective amount of a compound of formula I.
A further object of the invention is a method for the treatment and phophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi, whereby an effective amount of one of the compounds described above is administered.
Likewise an object of the invention are compounds described above for the treatment and prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infection caused by viruses, bacteria or fungi.
The conversion of a compound of formula I into a pharmaceutically usable salt can be carried out by treatment of such a compound with an inorganic acid, for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulphonic acid or p-toluenesulphonic acid.
The corresponding carboxylate salts can also be prepared from the compounds of formula I by treatment with physiologically compatible bases.
The conversion of a compound of formula I into a pharmaceutically usable ester can be accomplished by treatment of such a compound in the usual way e.g. with an alcohol in the presence of a catalytic amount of an acid like p-TsOH.
As mentioned previously, the compounds of formula I and their pharmaceutically usable salts inhibit especially the binding of various adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, etc.) on the surface of different types of cells. The said compounds therefore influence cell-cell and cell-matrix interactions. Since the vitronectin receptors play a role, inter alia, in the spread of tumor cell, in vascular regeneration, in the degradation of bone tissue, in the migration of smooth muscle cells in vascular walls and in the invasion of virus particles into target cells, the said compounds can be used as vitronectin receptor antagonists in the control or prevention of neoplasms, tumor metestasis, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, kidney failure as well as infections caused by viruses, bacteria or by fungi. Since the binding of the adhesive proteins to the fibrinogen receptor (xcex1IIbxcex23) on the surface of blood platelets is practically not inhibited, undesired side effects, such as e.g. bleeding, can be suppressed with the therapeutic application of the said compounds.
The inhibition of the binding of adhesive proteins such as e.g. fibrinogen to vitronectin receptors (such as e.g. xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, xcex1vxcex28, etc.) by compounds of the present invention can be determined as described by L. Alig et al. (J. Med. Chem. 1992, 35, 4393-4407).
In detail thereto, the wells of microtiter plates (Nunc-Immunoplate MaxiSorp) were coated overnight at 4xc2x0 C. with the vitronectin receptor xcex1vxcex23 (from human placenta, 100 xcexcl/well) in a buffer system with 150 mmol/l NaCl, 1 mmol/CaCl2, 1 mmol/l MgCl2, 0.0005% Triton X-100 and 20 mmol/l Tris HCl, pH 7.4. The non-specific binding sites were blocked by incubation with 3.5% bovine serum albumin (BSA from Fluka) at 20xc2x0 C. for at least 1 h. Before the beginning of the test the plates were washed in each case once with 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2 and 20 mmol/l Tris HCl, pH 7.4 (buffer A). The thus-coated plates can be stored for at least 2 months in the presence of 0.05% NaN3 (in buffer A) at 4xc2x0 C. in a humidity chamber without loss of binding activity. Fibrinogen (IMCO, free from fibronectin) was diluted to 1.5 xcexcg/ml in buffer A in the presence of 1% BSA. The wells coated with the receptor were incubated with fibrinogen (100 xcexcl/well) overnight at room temperature in the absence of or in the presence of increasing concentrations of RGDS (as the reference substance) or the compounds to be measured. Non-bound fibrinogen was removed by three-fold washing with buffer A, bound fibrinogen was detected by an ELISA procedure. Antibodies of rabbits directed against human fibrinogen (Dakopatts, Denmark), diluted in buffer A in the presence of 0.1% BSA, were added at room temperature for 1 h, followed by incubation with biotinylated antibodies directed against rabbit immunoglobulin (Amersham) for 30 min. Non-bound antibodies were removed by three-fold washing with buffer A. Thereafter, the pre-formed streptavidin-biotinylated peroxidase complex (Amersham) was added for 30 min. Three-fold washing with buffer A was again carried out. After addition of the peroxidase substrate ABTS (2,2xe2x80x2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), Boehringer Mannheim) the enzyme activity was measured with a multichannel photometer (UVmax, Molecular Devices). The difference between total binding activity (in the absence of a test substance) and non-specific binding activity (in the presence of 100 xcexcM RGDS) is taken as the specific binding activity.
The concentration of a test substance which is required to inhibit the specific binding activity by 50% was defined as the IC50.
The isolation of the receptor xcex1vxcex23 used in the test can be carried out as follows: Human placenta is stored at xe2x88x9280xc2x0 C. immediately after its excision. In order to extract the receptor, each placenta is superficially thawed and cut into narrow strips with a scalpel. The pieces are washed twice with a buffer of 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2 and 20 mmol/l Tris HCl (pH 7.4). The proteins are extracted at room temperature for one hour with a buffer solution from 1% Triton X-100, 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2, 20 mmol/l Tris HCl, 0.02% NaN3, 0.5 mmol/l phenylmethane-sulphonyl fluoride, 1 mmol/l leupeptin and 2 mmol/l N-ethylmaleimide (pH 7.4) and filtered through sterile gauze. The filtrate is centrifuged at 30000 g for 30 min. at 4xc2x0 C. The glycoproteins are firstly separated with the aid of a concanavalin A-Sepharose 4B column. The proteins bound to the column are eluted and then added to a Aeg-RGDS column. After repeated washing the bound vitronectin receptor is eluted by 3 mmol/l RGDS in a buffer of 0.1% Triton X-100, 150 mmol/l NaCl, 20 mmol/l Tris HCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2, 0.05% NaN3 (pH 7.0).
In the listings of specific compounds of formula I above, preferred compounds have IC50 values below 1000 nM and particularly preferred compounds have IC50 values below 10 nM. These results have been obtained by using the foregoing test.
The compounds of formula I and their pharmaceutically usable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
The compounds of formula I and their pharmaceutically usable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragxc3xa9es and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.
Suitable adjuvants for soft gelatin capsules, are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
In accordance with the invention the compounds of formula I and their pharmaceutically usable salts and esters can be used as vitronectin receptor antagonists especially for the treatment or prophylaxis of neoplasms, tumor metastasing, tumor growth, osteoporosis, Paget""s disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given above can be exceeded when this is shown to be indicated.
The disclosure of European Patent Application No. 99113708.4, filed Jul. 13, 1999, is incorporated herein by reference.